Efficient identification of novel mutations in patients with limb girdle muscular dystrophy

Steven E. Boyden, Mustafa A. Salih, Anna R. Duncan, Alexander J. White, Elicia A. Estrella, Stephanie L. Burgess, Mohammed Z. Seidahmed, Abdullah S. Al-Jarallah, Hisham M.S. Alkhalidi, Waleed M. Al-Maneea, Richard R. Bennett, Salem H. Alshemmari, Louis M. Kunkel, Peter B. Kang

Research output: Contribution to journalArticlepeer-review


Limb girdle muscular dystrophy type 2 (LGMD2) is a genetically heterogeneous autosomal recessive disorder caused by mutations in 15 known genes. DNA sequencing of all candidate genes can be expensive and laborious, whereas a selective sequencing approach often fails to provide a molecular diagnosis. We aimed to efficiently identify pathogenic mutations via homozygosity mapping in a population in which the genetics of LGMD2 has not been well characterized. Thirteen consanguineous families containing a proband with LGMD2 were recruited from Saudi Arabia, and for 11 of these families, selected individuals were genotyped at 10,204 single nucleotide polymorphisms. Linkage analysis excluded all but one or two known genes in ten of 11 genotyped families, and haplotype comparisons between families allowed further reduction in the number of candidate genes that were screened. Mutations were identified by DNA sequencing in all 13 families, including five novel mutations in four genes, by sequencing at most two genes per family. One family was reclassified as having a different myopathy based on genetic and clinical data after linkage analysis excluded all known LGMD2 genes. LGMD2 subtypes A and B were notably absent from our sample of patients, indicating that the distribution of LGMD2 mutations in Saudi Arabian families may be different than in other populations.Our data demonstrate that homozygositymapping in consanguineous pedigrees offers a more efficient means of discovering mutations that cause heterogeneous disorders than comprehensive sequencing of known candidate genes.

Original languageEnglish (US)
Pages (from-to)449-455
Number of pages7
Issue number4
StatePublished - Oct 2010
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank the patients and their families for their participation in this study and Kyriacos Markianos for helpful discussions. This work was supported by K08 NS048180 (PBK), the Genise Goldenson Fund (PBK), the Howard Hughes Medical Institute (LMK), the Manton Center for Orphan Disease Research (LMK), and the Bernard and Alva B. Gimbel Foundation (LMK). Microarray genotyping and DNA sequencing experiments were performed in the Molecular Genetics Core Facility at Children’s Hospital Boston, supported by NIH-P30-HD18655 through the Intellectual and Developmental Disabilities Research Center and NIH-P50-NS40828 through the Neuromuscular Disease Project.


  • Consanguineous
  • Homozygosity mapping
  • Limb girdle muscular dystrophy
  • Linkage analysis
  • Mutations
  • Saudi Arabian


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